Effects of 4-Ethylamino-2-butynyl(2-cyclohexyl-2-phenyl)glycolate Hydrochloride, a Metabolite of Oxybutynin, on Bladder Specimens and Rhythmic Bladder Contraction in Rats in Comparison With Oxybutynin

Abstract

Abstract. Oxybutynin has been used for neurogenic bladder disorders and is known to have anti-cholinergic and antispasmodic properties. However, the anti-cholinergic and antispasmodic properties of 4-ethylamino-2-butynyl(2-cyclohexyl-2-phenyl)glycolate hydrochloride (N-desethyloxybutynin: DEOB), a metabolite of oxybutynin, have not been clarified. Therefore, in the present study, we studied these properties by using rat urinary bladder specimens in comparison with oxybutynin. Moreover, the effect of DEOB on rhythmic urinary bladder contraction was also evaluated using anesthetized rats. DEOB and oxybutynin concentration-dependently inhibited the carbachol-induced contraction, the pA 2 values being 7.19 and 7.11, respectively. DEOB and oxybutynin also concentration-dependently inhibited the 100 mM KCl-induced contraction, the ED 50 values being 12.1 and 10.4 mM, respectively. Intravenously administered DEOB and oxybutynin dose-dependently (0.03 -0.3 mg / kg) inhibited the amplitude of the rhythmic bladder contraction to similar degrees, but had no affect on the frequency. From the above results, it was determined that DEOB has anti-cholinergic and antispasmodic properties and that these activities were almost equal to those of oxybutynin. Therefore, DEOB may play an important role during oxybutynin therapy for neurogenic bladder disorder.

In vivo demonstration of muscarinic receptor binding activity of N-desethyl-oxybutynin, active metabolite of oxybutynin

“…These data indicate that DEOB may display similar binding activity of muscarinic receptors in the rat bladder and submaxillary gland as oxybutynin under in vivo condition. This agrees with the pharmacological observation that DEOB and oxybutynin intravenously injected inhibited equipotently the rhythmic bladder contraction of anesthetized rats (Uchida et al, 2004). Also, the pilocarpine-induced salivary secretion in rats was equivalently suppressed at similar i.v.…”

“…The i.v. doses of DEOB and oxybutynin used here were determined on the basis of the pharmacologically relevant doses of these agents (Shimizu et al, 2001;Uchida et al, 2004).…”

Inhibitory effects of retigabine, a Kv7 channel activator, on mechanosensitive primary bladder afferent activities and nociceptive behaviors in rats

“…In the present study, the Kv7 channel activator retigabine dose‐dependently inhibited RBCs, and this inhibitory effect was more potent on RBC frequency than on the amplitude. Approximately 60–70 cmH 2 O of contraction‐amplitude during RBCs in the present study was relatively higher than those in previous reports using similar experiments of RBCs . We speculated that this discrepancy between the previous and present studies occurred due to different experimental conditions: e.g., different size of bladder catheters used, and/or conditions of saline‐instillation to induce/maintain RBCs.…”

Comparison of the effects of percutaneous and intraduodenal administration of oxybutynin on bladder contraction and salivation in rabbits

“…Intraperitoneally injected oxybutynin (3 mg/kg) and atropine (5 mg/kg) are known to shorten the ICI and reduce the PP in rats 6 . Recent studies have shown that oxybutynin decreases the frequency of isovolume bladder contractions and increases bladder capacity in anesthetized rabbits, but does not decrease the frequency of isovolume bladder contractions in anesthetized rats, while reducing the amplitude of the contraction in both species 8,9 . As our method allows voiding through the urethra, the time for which the bladder pressure rose to the urethral pressure was measured as the drug effect.…”

“…6 Recent studies have shown that oxybutynin decreases the frequency of isovolume bladder contractions and increases bladder capacity in anesthetized rabbits, but does not decrease the frequency of isovolume bladder contractions in anesthetized rats, while reducing the amplitude of the contraction in both species. 8,9 As our method allows voiding through the urethra, the time for which the bladder pressure rose to the urethral pressure was measured as the drug effect. To our knowledge, this is the first report describing the effects of oxybutynin on the continuous cystometrogram detected as ICI prolongation in an animal experiment.…”